Abstract
Previous work in our laboratories investigating compounds with structural similarity to ifenprodil (5) and 6 (CP101,606) resulted in compound 7 as a potent and selective antagonist of the NR1/2B subtype of the NMDA receptors. Replacement of the phenol group of 7 with a benzimidazalone group tethered by a three-carbon chain to 4-benzylpiperidine resulted in a slightly less active, but selective, compound. Lengthening the carbon tether resulted in a decrease in NR1/2B potency. Replacement of the phenol ring with a hydantoin resulted in weak antagonists. Compound 11a was one of the most potent NR1/2B antagonists from this study. Compound 11a also potentiated the effects of L-DOPA in a rat model of Parkinson's disease (the 6-hydroxydopamine-lesioned rat), dosed at 30 mg/kg orally.
MeSH terms
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Animals
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology
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Electrophysiology
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Excitatory Amino Acid Antagonists / chemical synthesis*
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Excitatory Amino Acid Antagonists / chemistry
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Excitatory Amino Acid Antagonists / pharmacology
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Hydantoins / chemical synthesis*
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Hydantoins / chemistry
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Hydantoins / pharmacology
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Hydrogen Bonding
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Male
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Oocytes / metabolism
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Oxidopamine
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Parkinson Disease, Secondary / chemically induced
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Parkinson Disease, Secondary / drug therapy
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Piperidines / chemistry
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Piperidines / pharmacology
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RNA, Messenger / biosynthesis
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Rats
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Rats, Sprague-Dawley
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
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Receptors, N-Methyl-D-Aspartate / biosynthesis
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Sympatholytics
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Xenopus
Substances
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Benzimidazoles
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Excitatory Amino Acid Antagonists
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Hydantoins
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Neuroprotective Agents
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Piperidines
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RNA, Messenger
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Receptors, N-Methyl-D-Aspartate
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Sympatholytics
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Oxidopamine
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ifenprodil